Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch
Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch
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DOI：
10.7554/elife.11878
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发表时间：
2016-07-20
期刊：
影响因子：
7.7
通讯作者：
Walter, Peter
中科院分区：
文献类型：
--
作者：
Gallagher, Ciara M.;Garri, Carolina;Walter, Peter
膜结合转录因子ATF6 α在未折叠蛋白反应（UPR）中起细胞保护作用，这是细胞在ER应激中存活所需的。ATF6 α的激活促进癌症模型中的细胞存活。我们使用基于细胞的筛选来发现和开发Ceapins，Ceapins是一类吡唑酰胺，其阻断响应于ER应激的ATF6 α信号传导。Ceapins使细胞对ER应激敏感而不影响未应激细胞的活力。Ceapins是ATF6 α信号传导的高度特异性抑制剂，不影响通过UPR的其他分支的信号传导，或其紧密同系物ATF6 β或SREBP（胆固醇调节的转录因子）的蛋白水解加工，两者都由相同的蛋白酶激活。Ceapins是一流的抑制剂，可用于探索ATF6 α的激活机制及其在病理环境中的作用。Ceapins的发现现在能够单独或组合地药理学调节所有三个UPR分支。
The membrane-bound transcription factor ATF6 alpha plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6 alpha promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6 alpha signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6 alpha signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6 beta or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6 alpha and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination.